Warnings and Precautions Never Share a Humalog KwikPen, Cartridge, Reusable Pen Compatible with Lilly 3 ml Cartridges, or Syringe Between

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1 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use HUMALOG sfely nd effectively. See full prescriing informtion for HUMALOG. HUMALOG (insulin lispro injection), for sucutneous or intrvenous use Initil U.S. Approvl: RECENT MAJOR CHANGES Dosge nd Administrtion (2.1, 2.2, 2.3, 2.4) 05/2015 Wrnings nd Precutions Never Shre Humlog KwikPen, Crtridge, Reusle Pen Comptile with Lilly 3 ml Crtridges, or Syringe Between Ptients (5.1) 02/2015 Hypoglycemi Due to Mediction Errors (5.4) 05/ INDICATIONS AND USAGE HUMALOG is rpid cting humn insulin nlog indicted to improve glycemic control in dults nd children with dietes mellitus. (1) DOSAGE AND ADMINISTRATION See Full Prescriing Informtion for importnt dministrtion instructions. (2.1, 2.2, 2.3, 2.4) Sucutneous injection: Administer HUMALOG U-100 or U-200 y sucutneous injection within 15 minutes efore mel or immeditely fter mel. (2.2) Continuous sucutneous infusion (Insulin Pump): Administer HUMALOG U-100 y continuous sucutneous infusion using n insulin pump. DO NOT dminister HUMALOG U-200 y continuous sucutneous infusion. (2.2) Intrvenous Infusion: Administer HUMALOG U-100 y intrvenous infusion ONLY fter dilution nd under medicl supervision. DO NOT dminister HUMALOG U-200 y intrvenous infusion. (2.2) The dosge of HUMALOG must e individulized sed on the route of dministrtion nd the individul's metolic needs, lood glucose monitoring results nd glycemic control gol. (2.3) Do not perform dose conversion when using the HUMALOG U-100 or U-200 KwikPens. The dose window shows the numer of insulin units to e delivered nd no conversion is needed. (2.1, 2.3) Do not mix HUMALOG U-200 with ny other insulin. (2.4) DOSAGE FORMS AND STRENGTHS HUMALOG 100 units/ml (U-100) is ville s: (3) 10 ml vils 3 ml vils 3 ml Humlog KwikPen (prefilled) 3 ml crtridges HUMALOG 200 units/ml (U-200) is ville s: (3) 3 ml Humlog KwikPen (prefilled) CONTRAINDICATIONS Do not use during episodes of hypoglycemi. (4) Do not use in ptients with hypersensitivity to HUMALOG or ny of its excipients. (4) WARNINGS AND PRECAUTIONS Never shre HUMALOG KwikPen, crtridge, reusle pen comptile with Lilly 3 ml crtridges, or syringe etween ptients, even if the needle is chnged. (5.1) Hyper- or Hypoglycemi with Chnges in Insulin Regimen: Crry out under close medicl supervision nd increse frequency of lood glucose monitoring. (5.2) Hypoglycemi: My e life-thretening. Monitor lood glucose nd increse monitoring frequency with chnges to insulin dosge, use of glucose lowering medictions, mel pttern, physicl ctivity; in ptients with renl or heptic impirment; nd in ptients with hypoglycemi unwreness. (5.3, 7, 8.6, 8.7) Hypoglycemi Due to Mediction Errors: Accidentl mix-ups etween insulin products cn occur. Instruct ptients to check insulin lels efore injection. Do not trnsfer HUMALOG U-200 from the HUMALOG KwikPen to syringe s overdosge nd severe hypoglycemi cn result. (5.4) Hypersensitivity Rections: My e life-thretening. Discontinue HUMALOG, monitor nd tret if indicted. (5.5) Hypoklemi: My e life-thretening. Monitor potssium levels in ptients t risk of hypoklemi nd tret if indicted. (5.6) Fluid Retention nd Hert Filure with Concomitnt Use of Thizolidinediones (TZDs): Oserve for signs nd symptoms of hert filure; consider dosge reduction or discontinution if hert filure occurs. (5.7) Hyperglycemi nd Ketocidosis Due to Insulin Pump Device Mlfunction: Monitor glucose nd dminister HUMALOG U-100 y sucutneous injection if pump mlfunction occurs. (5.8) ADVERSE REACTIONS Adverse rections ssocited with HUMALOG include hypoglycemi, llergic rections, injection site rections, lipodystrophy, pruritus, nd rsh. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t LillyRx ( ) or FDA t 1-800FDA-1088 or DRUG INTERACTIONS Drugs tht Affect Glucose Metolism: Adjustment of insulin dosge my e needed. (7.1, 7.2, 7.3) Anti-Adrenergic Drugs (e.g., et-lockers, clonidine, gunethidine, nd reserpine): Signs nd symptoms of hypoglycemi my e reduced or sent. (5.3, 7.4) USE IN SPECIFIC POPULATIONS Peditrics: Not studied in children with type 2 dietes or in children with type 1 dietes <3 yers of ge. (8.4) See 17 for PATIENT COUNSELING INFORMATION nd FDApproved ptient leling Revised: 11/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Importnt Administrtion Instructions 2.2 Route of Administrtion 2.3 Dosge Informtion 2.4 Dosge Adjustment Due to Drug Interctions Hypoklemi Fluid Retention nd Hert Filure with Concomitnt Use of PPAR-gmm Agonists Hyperglycemi nd Ketocidosis Due to Insulin Pump Device Mlfunction 6 ADVERSE REACTIONS 6.1 Clinicl Tril Experience 6.2 Postmrketing Experience 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 7 5 WARNINGS AND PRECAUTIONS 5.1 Never Shre HUMALOG KwikPen, Crtridge, Reusle 1 Pen Comptile with Lilly 3 ml Crtridges, or Syringe Between Ptients 5.2 Hyper- or Hypoglycemi with Chnges in Insulin Regimen 5.3 Hypoglycemi 5.4 Hypoglycemi Due to Mediction Errors 5.5 Hypersensitivity Rections DRUG INTERACTIONS 7.1 Drugs Tht My Increse the Risk of Hypoglycemi 7.2 Drugs Tht My Decrese the Blood Glucose Lowering Effect of HUMALOG 7.3 Drugs Tht My Increse or Decrese the Blood Glucose Lowering Effect of HUMALOG 7.4 Drugs Tht My Blunt Signs nd Symptoms of Hypoglycemi 8 USE IN SPECIFIC POPULATIONS

2 Pregnncy Nursing Mothers Peditric Use Geritric Use Renl Impirment Heptic Impirment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxicology nd/or Phrmcology 14 CLINICAL STUDIES 14.1 Type 1 Dietes Adults nd Adolescents 14.2 Type 2 Dietes Adults 14.3 Type 1 Dietes Peditric nd Adolescents 14.4 Type 1 Dietes Adults Continuous Sucutneous Insulin Infusion 14.5 Type 1 Dietes Peditric Continuous Sucutneous Insulin Infusion 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storge nd Hndling 16.3 Preprtion nd Hndling 16.4 Admixture for Intrvenous Administrtion 17 PATIENT COUNSELING INFORMATION 17.1 Never Shre HUMALOG KwikPen, Crtridge, Reusle Pen Comptile with Lilly 3 ml Crtridges, or Syringe Between Ptients 17.2 Hypoglycemi 17.3 Hypersensitivity Rections 17.4 Mediction Errors 17.5 Administrtion Instruction for HUMALOG U Women of Reproductive Potentil 17.7 Instructions For Ptients Using Continuous Sucutneous Insulin Pumps * Sections or susections omitted from the full prescriing informtion re not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE HUMALOG is rpid cting humn insulin nlog indicted to improve glycemic control in dults nd children with dietes mellitus DOSAGE AND ADMINISTRATION Importnt Administrtion Instructions Alwys check insulin lels efore dministrtion [see Wrnings nd Precutions (5.4)]. Inspect HUMALOG visully efore use. It should pper cler nd colorless. Do not use HUMALOG if prticulte mtter or colortion is seen. Do NOT mix HUMALOG U-100 with other insulins when dministering using continuous sucutneous infusion pump. Do NOT trnsfer HUMALOG U-200 from the KwikPen to syringe for dministrtion [see Wrnings nd Precutions (5.4)]. Do NOT perform dose conversion when using either the HUMALOG U-100 or U-200 KwikPens. The dose window shows the numer of insulin units to e delivered nd no conversion is needed. Do NOT mix HUMALOG U-200 with ny other insulins. Do NOT dminister HUMALOG U-200 using continuous sucutneous infusion pump (i.e., insulin pump). Do NOT dminister HUMALOG U-200 intrvenously. Route of Administrtion Sucutneous Injection: HUMALOG U-100 or U-200 Administer the dose of HUMALOG U-100 or HUMALOG U-200 within fifteen minutes efore mel or immeditely fter mel y injection into the sucutneous tissue of the dominl wll, thigh, upper rm, or uttocks. To reduce the risk of lipodystrophy, rotte the injection site within the sme region from one injection to the next [see Adverse Rections (6)]. HUMALOG dministered y sucutneous injection should generlly e used in regimens with n intermedite- or long-cting insulin. Continuous Sucutneous Infusion (Insulin Pump): HUMALOG U-100 ONLY Do NOT dminister HUMALOG U-200 using continuous sucutneous infusion pump. Administer HUMALOG U-100 y continuous sucutneous infusion into the sucutneous tissue of the dominl wll. Rotte infusion sites within the sme region to reduce the risk of lipodystrophy [see Adverse Rections (6.1)]. Follow helthcre professionl recommendtions when setting sl nd mel time infusion rte. Do NOT dilute or mix HUMALOG U-100 when dministering y continuous sucutneous infusion. Chnge HUMALOG U-100 in the pump reservoir t lest every 7 dys. Chnge the infusion sets nd the infusion set insertion site t lest every 3 dys. Do NOT expose HUMALOG U-100 in the pump reservoir to tempertures greter thn 98.6 F (37 C). Use HUMALOG U-100 in pump systems suitle for insulin infusion [see Ptient Counseling Informtion (17.7)]. Intrvenous Administrtion: HUMALOG U-100 ONLY Do NOT dminister HUMALOG U-200 intrvenously.

3 Dilute HUMALOG U-100 to concentrtions from 0.1 unit/ml to 1.0 unit/ml using 0.9% sodium chloride. Administer HUMALOG U-100 intrvenously ONLY under medicl supervision with close monitoring of lood glucose nd potssium levels to void hypoglycemi nd hypoklemi [see Wrnings nd Precutions (5.3, 5.6) nd How Supplied/Storge nd Hndling (16.4)]. Dosge Informtion Individulize nd djust the dosge of HUMALOG sed on route of dministrtion, the individul's metolic needs, lood glucose monitoring results nd glycemic control gol. Dosge djustments my e needed with chnges in physicl ctivity, chnges in mel ptterns (i.e., mcronutrient content or timing of food intke), chnges in renl or heptic function or during cute illness [see Wrnings nd Precutions (5.2, 5.3) nd Use in Specific Popultions (8.6, 8.7)]. Do NOT perform dose conversion when using either the HUMALOG U-100 or U-200 KwikPens. The dose window shows the numer of insulin units to e delivered nd no conversion is needed. Dosge Adjustment Due to Drug Interctions Dosge djustment my e needed when HUMALOG is codministered with certin drugs [see Drug Interctions (7)]. Dosge djustment my e needed when switching from nother insulin to HUMALOG [see Wrnings nd Precutions (5.2)]. Instructions for Mixing with Other Insulins HUMALOG U-100 sucutneous injection route HUMALOG U-100 continuous sucutneous infusion route (Insulin Pump) HUMALOG U-200 sucutneous injection route HUMALOG U-100 my e mixed with NPH insulin preprtions ONLY. If HUMALOG U-100 is mixed with NPH insulin, HUMALOG U-100 should e drwn into the syringe first. Injection should occur immeditely fter mixing. Do NOT mix HUMALOG U-100 with ny other insulin. Do NOT mix with ny other insulin. 3 DOSAGE FORMS AND STRENGTHS HUMALOG 100 units per ml (U-100) is ville s: 10 ml vils 3 ml vils 3 ml Humlog KwikPen (prefilled) 3 ml crtridges HUMALOG 200 units per ml (U-200) is ville s: 3 ml Humlog KwikPen (prefilled) 4 CONTRAINDICATIONS HUMALOG is contrindicted: during episodes of hypoglycemi in ptients who re hypersensitive to HUMALOG or to ny of its excipients. 5 WARNINGS AND PRECAUTIONS 5.1 Never Shre HUMALOG KwikPen, Crtridge, Reusle Pen Comptile with Lilly 3 ml Crtridges1, or Syringe Between Ptients HUMALOG KwikPens, crtridges, nd reusle pens comptile with Lilly 3 ml crtridges must never e shred etween ptients, even if the needle is chnged. Ptients using HUMALOG vils must never shre needles or syringes with nother person. Shring poses risk for trnsmission of lood-orne pthogens. 5.2 Hyper- or Hypoglycemi with Chnges in Insulin Regimen Chnges in insulin strength, mnufcturer, type, or method of dministrtion my ffect glycemic control nd predispose to hypoglycemi [see Wrnings nd Precutions (5.3)] or hyperglycemi. These chnges should e mde cutiously nd under close medicl supervision nd the frequency of lood glucose monitoring should e incresed. 5.3 Hypoglycemi Hypoglycemi is the most common dverse rection ssocited with insulins, including HUMALOG. Severe hypoglycemi cn cuse seizures, my e life-thretening, or cuse deth. Hypoglycemi cn impir concentrtion ility nd rection time; this my plce n individul nd others t risk in situtions where these ilities re importnt (e.g., driving or operting other mchinery).

4 4 Hypoglycemi cn hppen suddenly nd symptoms my differ in ech individul nd chnge over time in the sme individul. Symptomtic wreness of hypoglycemi my e less pronounced in ptients with longstnding dietes, in ptients with dietic nerve disese, in ptients using medictions tht lock the sympthetic nervous system (e.g., et-lockers) [see Drug Interctions (7)], or in ptients who experience recurrent hypoglycemi. Risk Fctors for Hypoglycemi The risk of hypoglycemi fter n injection is relted to the durtion of ction of the insulin nd, in generl, is highest when the glucose lowering effect of the insulin is mximl. As with ll insulin preprtions, the glucose lowering effect time course of HUMALOG my vry in different individuls or t different times in the sme individul nd depends on mny conditions, including the re of injection s well s the injection site lood supply nd temperture [see Clinicl Phrmcology (12.2)]. Other fctors which my increse the risk of hypoglycemi include chnges in mel pttern (e.g., mcronutrient content or timing of mels), chnges in level of physicl ctivity, or chnges to co-dministered mediction [see Drug Interctions (7)]. Ptients with renl or heptic impirment my e t higher risk of hypoglycemi [see Use in Specific Popultions (8.6, 8.7)]. Risk Mitigtion Strtegies for Hypoglycemi Ptients nd cregivers must e educted to recognize nd mnge hypoglycemi. Self-monitoring of lood glucose plys n essentil role in the prevention nd mngement of hypoglycemi. In ptients t higher risk for hypoglycemi nd ptients who hve reduced symptomtic wreness of hypoglycemi, incresed frequency of lood glucose monitoring is recommended. 5.4 Hypoglycemi Due to Mediction Errors Accidentl mix-ups etween sl insulin products nd other insulins, prticulrly rpid-cting insulins, hve een reported. To void mediction errors etween HUMALOG nd other insulins, instruct ptients to lwys check the insulin lel efore ech injection. Do not trnsfer HUMALOG U-200 from the HUMALOG KwikPen to syringe. The mrkings on the insulin syringe will not mesure the dose correctly nd cn result in overdosge nd severe hypoglycemi [see Dosge nd Administrtion (2.1) nd Wrnings nd Precutions (5.3)]. 5.5 Hypersensitivity Rections Severe, life-thretening, generlized llergy, including nphylxis, cn occur with insulin products, including HUMALOG. If hypersensitivity rections occur, discontinue HUMALOG; tret per stndrd of cre nd monitor until symptoms nd signs resolve [see Adverse Rections (6.1)]. HUMALOG is contrindicted in ptients who hve hd hypersensitivity rections to HUMALOG or ny of its excipients [see Contrindictions (4)]. 5.6 Hypoklemi All insulin products, including HUMALOG, cuse shift in potssium from the extrcellulr to intrcellulr spce, possily leding to hypoklemi. Untreted hypoklemi my cuse respirtory prlysis, ventriculr rrhythmi, nd deth. Monitor potssium levels in ptients t risk for hypoklemi if indicted (e.g., ptients using potssium-lowering medictions, ptients tking medictions sensitive to serum potssium concentrtions). 5.7 Fluid Retention nd Hert Filure with Concomitnt Use of PPAR-gmm Agonists Thizolidinediones (TZDs), which re peroxisome prolifertor-ctivted receptor (PPAR)-gmm gonists, cn cuse dose-relted fluid retention, prticulrly when used in comintion with insulin. Fluid retention my led to or excerte hert filure. Ptients treted with insulin, including HUMALOG, nd PPAR-gmm gonist should e oserved for signs nd symptoms of hert filure. If hert filure develops, it should e mnged ccording to current stndrds of cre, nd discontinution or dose reduction of the PPAR-gmm gonist must e considered. 5.8 Hyperglycemi nd Ketocidosis Due to Insulin Pump Device Mlfunction Mlfunction of the insulin pump or insulin infusion set or insulin degrdtion cn rpidly led to hyperglycemi nd ketocidosis. Prompt identifiction nd correction of the cuse of hyperglycemi or ketosis is necessry. Interim sucutneous injections with HUMALOG my e required. Ptients using continuous sucutneous insulin infusion pump therpy must e trined to dminister insulin y injection nd hve lternte insulin therpy ville in cse of pump filure [see How Supplied/Storge nd Hndling (16.2) nd Ptient Counseling Informtion (17.7)]. 6 ADVERSE REACTIONS Oserved with HUMALOG U-100 The following dverse rections re discussed elsewhere: Hypoglycemi [see Wrnings nd Precutions (5.3)]. Hypoklemi [see Wrnings nd Precutions (5.6)]. 6.1 Clinicl Tril Experience Becuse clinicl trils re conducted under widely vrying designs, the dverse rection rtes reported in one clinicl tril my not e esily compred with those rtes reported in nother clinicl tril, nd my not reflect the rtes ctully oserved in clinicl prctice. The frequencies of Tretment-Emergent Adverse Events during HUMALOG clinicl trils in ptients with type 1 dietes mellitus nd type 2 dietes mellitus re listed in the tles elow.

5 Tle 1: Tretment-Emergent Adverse Events in Ptients with Type 1 Dietes Mellitus (dverse events with frequency 5%) Events, n (%) Lispro Regulr humn insulin (n=81) (n=86) Flu syndrome 28 (34.6) 28 (32.6) Phryngitis 27 (33.3) 29 (33.7) Rhinitis 20 (24.7) 25 (29.1) Hedche 24 (29.6) 19 (22.1) Pin 16 (19.8) 14 (16.3) Cough incresed 14 (17.3) 15 (17.4) Infection 11 (13.6) 18 (20.9) Nuse 5 (6.2) 13 (15.1) Accidentl injury 7 (8.6) 10 (11.6) Surgicl procedure 5 (6.2) 12 (14.0) Fever 5 (6.2) 10 (11.6) Adominl pin 6 (7.4) 7 (8.1) Astheni 6 (7.4) 7 (8.1) Bronchitis 6 (7.4) 6 (7.0) Dirrhe 7 (8.6) 5 (5.8) Dysmenorrhe 5 (6.2) 6 (7.0) Mylgi 6 (7.4) 5 (5.8) Urinry trct infection 5 (6.2) 4 (4.7) 5 Tle 2: Tretment-Emergent Adverse Events in Ptients with Type 2 Dietes Mellitus (dverse events with frequency 5%) Events, n (%) Lispro Regulr humn insulin (n=714) (n=709) Hedche 63 (11.6) 66 (9.3) Pin 77 (10.8) 71 (10.0) Infection 72 (10.1) 54 (7.6) Phryngitis 47 (6.6) 58 (8.2) Rhinitis 58 (8.1) 47 (6.6) Flu syndrome 44 (6.2) 58 (8.2) Surgicl procedure 53 (7.4) 48 (6.8) Insulin initition nd intensifiction of glucose control Intensifiction or rpid improvement in glucose control hs een ssocited with trnsitory, reversile ophthlmologic refrction disorder, worsening of dietic retinopthy, nd cute pinful peripherl neuropthy. However, long-term glycemic control decreses the risk of dietic retinopthy nd neuropthy. Lipodystrophy Long-term use of insulin, including HUMALOG, cn cuse lipodystrophy t the site of repeted insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of dipose tissue) nd lipotrophy (thinning of dipose tissue), nd my ffect insulin sorption. Rotte insulin injection or infusion sites within the sme region to reduce the risk of lipodystrophy [see Dosge nd Administrtion (2.2)]. Weight gin Weight gin cn occur with insulin therpy, including HUMALOG, nd hs een ttriuted to the nolic effects of insulin nd the decrese in glucosuri. Peripherl Edem Insulin, including HUMALOG, my cuse sodium retention nd edem, prticulrly if previously poor metolic control is improved y intensified insulin therpy. Adverse Rections with Continuous Sucutneous Insulin Infusion (CSII) HUMALOG U-100 In 12-week, rndomized, crossover study in dult ptients with type 1 dietes (n=39), the rtes of ctheter occlusions nd infusion site rections were similr for HUMALOG U-100 nd regulr humn insulin treted ptients (see Tle 3). Ctheter occlusions/month Tle 3: Ctheter Occlusions nd Infusion Site Rections HUMALOG U-100 Regulr humn insulin (n=38) (n=39)

6 6 Infusion site rections 2.6% (1/38) 2.6% (1/39) In rndomized, 16-week, open-lel, prllel design study of children nd dolescents with type 1 dietes, dverse event reports relted to infusion-site rections were similr for insulin lispro nd insulin sprt (21% of 100 ptients versus 17% of 198 ptients, respectively). In oth groups, the most frequently reported infusion site dverse events were infusion site erythem nd infusion site rection. Allergic Rections Locl Allergy As with ny insulin therpy, ptients tking HUMALOG my experience redness, swelling, or itching t the site of the injection. These minor rections usully resolve in few dys to few weeks, ut in some occsions, my require discontinution of HUMALOG. In some instnces, these rections my e relted to fctors other thn insulin, such s irritnts in skin clensing gent or poor injection technique. Systemic Allergy Severe, life-thretening, generlized llergy, including nphylxis, my occur with ny insulin, including HUMALOG. Generlized llergy to insulin my cuse whole ody rsh (including pruritus), dyspne, wheezing, hypotension, tchycrdi, or diphoresis. In controlled clinicl trils, pruritus (with or without rsh) ws seen in 17 ptients receiving regulr humn insulin (n=2969) nd 30 ptients receiving HUMALOG (n=2944). Loclized rections nd generlized mylgis hve een reported with injected metcresol, which is n excipient in HUMALOG [see Contrindictions (4)]. Antiody Production In lrge clinicl trils with ptients with type 1 (n=509) nd type 2 (n=262) dietes mellitus, nti-insulin ntiody (insulin lispro-specific ntiodies, insulin-specific ntiodies, cross-rective ntiodies) formtion ws evluted in ptients receiving oth regulr humn insulin nd HUMALOG (including ptients previously treted with humn insulin nd nive ptients). As expected, the lrgest increse in the ntiody levels occurred in ptients new to insulin therpy. The ntiody levels peked y 12 months nd declined over the remining yers of the study. These ntiodies do not pper to cuse deteriortion in glycemic control or necessitte n increse in insulin dose. There ws no sttisticlly significnt reltionship etween the chnge in the totl dily insulin dose nd the chnge in percent ntiody inding for ny of the ntiody types. 6.2 Postmrketing Experience HUMALOG U-100 The following dditionl dverse rections hve een identified during post-pprovl use of HUMALOG. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possile to relily estimte their frequency or estlish cusl reltionship to drug exposure. Mediction errors in which other insulins hve een ccidentlly sustituted for HUMALOG hve een identified during postpprovl use [see Ptient Counseling Informtion (17.4)] DRUG INTERACTIONS Drugs Tht My Increse the Risk of Hypoglycemi The risk of hypoglycemi ssocited with HUMALOG use my e incresed when co-dministered with ntidietic gents, slicyltes, sulfonmide ntiiotics, monomine oxidse inhiitors, fluoxetine, prmlintide, disopyrmide, firtes, propoxyphene, pentoxifylline, ACE inhiitors, ngiotensin II receptor locking gents, nd somtosttin nlogs (e.g., octreotide). Dose djustment nd incresed frequency of glucose monitoring my e required when HUMALOG is co-dministered with these drugs. 7.2 Drugs Tht My Decrese the Blood Glucose Lowering Effect of HUMALOG The glucose lowering effect of HUMALOG my e decresed when co-dministered with corticosteroids, isonizid, nicin, estrogens, orl contrceptives, phenothizines, dnzol, diuretics, sympthomimetic gents (e.g., epinephrine, luterol, terutline), somtropin, typicl ntipsychotics, glucgon, protese inhiitors, nd thyroid hormones. Dose djustment nd incresed frequency of glucose monitoring my e required when HUMALOG is co-dministered with these drugs. 7.3 Drugs Tht My Increse or Decrese the Blood Glucose Lowering Effect of HUMALOG The glucose lowering effect of HUMALOG my e incresed or decresed with co-dministered with etlockers, clonidine, lithium slts, nd lcohol. Pentmidine my cuse hypoglycemi, which my sometimes e followed y hyperglycemi. Dose djustment nd incresed frequency of glucose monitoring my e required when HUMALOG is co-dministered with these drugs. 7.4 Drugs Tht My Blunt Signs nd Symptoms of Hypoglycemi The signs nd symptoms of hypoglycemi [see Wrnings nd Precutions (5.3)] my e lunted when etlockers, clonidine, gunethidine, nd reserpine re co-dministered with HUMALOG USE IN SPECIFIC POPULATIONS Pregnncy

7 7 Pregnncy Ctegory B. All pregnncies hve ckground risk of irth defects, loss, or other dverse outcome regrdless of drug exposure. This ckground risk is incresed in pregnncies complicted y hyperglycemi nd my e decresed with good metolic control. It is essentil for ptients with dietes or history of gesttionl dietes to mintin good metolic control efore conception nd throughout pregnncy. In ptients with dietes or gesttionl dietes insulin requirements my decrese during the first trimester, generlly increse during the second nd third trimesters, nd rpidly decline fter delivery. Creful monitoring of glucose control is essentil in these ptients. Therefore, femle ptients should e dvised to tell their physicins if they intend to ecome, or if they ecome pregnnt while tking HUMALOG. Although there re limited clinicl studies of the use of HUMALOG in pregnncy, pulished studies with humn insulins suggest tht optimizing overll glycemic control, including postprndil control, efore conception nd during pregnncy improves fetl outcome. In comined fertility nd emryo-fetl development study, femle rts were given sucutneous insulin lispro injections of 5 nd 20 units/kg/dy (0.8 nd 3 times the humn sucutneous dose of 1 unit/kg/dy, sed on units/ody surfce re, respectively) from 2 weeks prior to cohittion through Gesttion Dy 19. There were no dverse effects on femle fertility, implnttion, or fetl viility nd morphology. However, fetl growth retrdtion ws produced t the 20 units/kg/dy-dose s indicted y decresed fetl weight nd n incresed incidence of fetl runts/litter. In n emryo-fetl development study in pregnnt rits, insulin lispro doses of 0.1, 0.25, nd 0.75 unit/kg/dy (0.03, 0.08, nd 0.24 times the humn sucutneous dose of 1 unit/kg/dy, sed on units/ody surfce re, respectively) were injected sucutneously on Gesttion dys 7 through 19. There were no dverse effects on fetl viility, weight, nd morphology t ny dose. 8.3 Nursing Mothers It is unknown whether insulin lispro is excreted in humn milk. Becuse mny drugs re excreted in humn milk, cution should e exercised when HUMALOG is dministered to nursing womn. Use of HUMALOG is comptile with restfeeding, ut women with dietes who re lctting my require djustments of their insulin doses. 8.4 Peditric Use HUMALOG is pproved for use in children for sucutneous dily injections [see Clinicl Studies (14)]. Only the U-100 formultion of HUMALOG is pproved for use in children y continuous sucutneous infusion in insulin pumps. HUMALOG hs not een studied in peditric ptients younger thn 3 yers of ge. HUMALOG hs not een studied in peditric ptients with type 2 dietes. As in dults, the dosge of HUMALOG must e individulized in peditric ptients sed on metolic needs nd results of frequent monitoring of lood glucose. 8.5 Geritric Use Of the totl numer of sujects (n=2834) in eight clinicl studies of HUMALOG, twelve percent (n=338) were 65 yers of ge or over. The mjority of these hd type 2 dietes. HA1c vlues nd hypoglycemi rtes did not differ y ge. Phrmcokinetic/phrmcodynmic studies to ssess the effect of ge on the onset of HUMALOG ction hv e not een performed. 8.6 Renl Impirment Ptients with renl impirment my e t incresed risk of hypoglycemi nd my require more frequent HUMALOG dose djustment nd more frequent lood glucose monitoring [see Clinicl Phrmcology (12.3)]. 8.7 Heptic Impirment Ptients with heptic impirment my e t incresed risk of hypoglycemi nd my require more frequent HUMALOG dose djustment nd more frequent lood glucose monitoring [see Clinicl Phrmcology (12.3)]. 10 OVERDOSAGE Excess insulin dministrtion my cuse hypoglycemi nd hypoklemi. Mild episodes of hypoglycemi usully cn e treted with orl glucose. Adjustments in drug dosge, mel ptterns, or exercise my e needed. More severe episodes with com, seizure, or neurologic impirment my e treted with intrmusculr/sucutneous glucgon or concentrted intrvenous glucose. Sustined crohydrte intke nd oservtion my e necessry ecuse hypoglycemi my recur fter pprent clinicl recovery. Hypoklemi must e corrected ppropritely. 11 DESCRIPTION HUMALOG (insulin lispro injection) is rpid-cting humn insulin nlog used to lower lood glucose. Insulin lispro is produced y recominnt DNA technology utilizing non-pthogenic lortory strin of Escherichi coli. Insulin lispro differs from humn insulin in tht the mino cid proline t position B28 is replced y lysine nd the lysine in position B29 is replced y proline. Chemiclly, it is Lys(B28), Pro(B29) humn insulin nlog nd hs the empiricl formul C257H383N65O77S6 nd moleculr weight of 5808, oth identicl to tht of humn insulin.

8 8 HUMALOG hs the following primry structure: HUMALOG is sterile, queous, cler, nd colorless solution. Ech milliliter of HUMALOG U-100 contins insulin lispro 100 units, 16 mg glycerin, 1.88 mg disic sodium phosphte, 3.15 mg Metcresol, zinc oxide content djusted to provide mg zinc ion, trce mounts of phenol, nd Wter for Injection. Insulin lispro hs ph of 7.0 to 7.8. The ph is djusted y ddition of queous solutions of hydrochloric cid 10% nd/or sodium hydroxide 10%. Ech milliliter of HUMALOG U-200 contins insulin lispro 200 units, 16 mg glycerin, 5 mg tromethmine, 3.15 mg Metcresol, zinc oxide content djusted to provide mg zinc ion, trce mounts of phenol, nd Wter for Injection. Insulin lispro hs ph of 7.0 to 7.8. The ph is djusted y ddition of queous solutions of hydrochloric cid 10% nd/or sodium hydroxide 10% CLINICAL PHARMACOLOGY Mechnism of Action Regultion of glucose metolism is the primry ctivity of insulins nd insulin nlogs, including insulin lispro. Insulins lower lood glucose y stimulting peripherl glucose uptke y skeletl muscle nd ft, nd y inhiiting heptic glucose production. Insulins inhiit lipolysis nd proteolysis, nd enhnce protein synthesis Phrmcodynmics HUMALOG hs een shown to e equipotent to humn insulin on molr sis. One unit of HUMALOG hs the sme glucose-lowering effect s one unit of regulr humn insulin. Studies in norml volunteers nd ptients with dietes demonstrted tht HUMALOG hs more rpid onset of ction nd shorter durtion of ctivity thn regulr humn insulin when given sucutneously. The time course of ction of insulin nd insulin nlogs, such s HUMALOG, my vry considerly in different individuls or within the sme individul. The prmeters of HUMALOG ctivity (time of onset, pek time, nd durtion) s designted in Figure 1 should e considered only s generl guidelines. The rte of insulin sorption, nd consequently the onset of ctivity re known to e ffected y the site of injection, exercise, nd other vriles [see Wrnings nd Precutions (5.2)]. Figure 1: Blood Glucose Levels After Sucutneous Injection of Regulr Humn Insulin or HUMALOG (0.2 unit/kg) Immeditely Before High Crohydrte Mel in 10 Ptients with Type 1 Dietes. Bseline insulin concentrtion ws mintined y infusion of 0.2 mu/min/kg humn insulin. Intrvenous Administrtion of HUMALOG U-100 The glucose lowering effect of intrvenously dministered HUMALOG ws tested in 21 ptients with type 1 dietes. For the study, the ptients usul doses of insulin were held nd lood glucose concentrtions were llowed to rech stle rnge of 200 to 260 mg/dl during one to three hours run-in phse. The run-in phse ws followed y 6-hour ssessment phse. During the ssessment phse, ptients

9 9 received intrvenous HUMALOG t n initil infusion rte of 0.5 units/hour. The infusion rte of HUMALOG could e djusted t regulr timed intervls to chieve nd mintin lood glucose concentrtions etween 100 to 160 mg/dl. The men lood glucose levels during the ssessment phse for ptients on HUMALOG therpy re summrized elow in Tle 4. All ptients chieved the trgeted glucose rnge t some point during the 6-hour ssessment phse. At the endpoint, lood glucose ws within the trget rnge (100 to 160 mg/dl) for 17 of 20 ptients treted with HUMALOG. The verge time (±SE) required to ttin ner normoglycemi ws 129 ± 14 minutes for HUMALOG. Tle 4: Men Blood Glucose Concentrtions (mg/dl) During Intrvenous Infusions of HUMALOG U-100 Time from Strt of Infusion (minutes) Men Blood Glucose (mg/dl) Intrvenous ± ± ± ± ± ± ± ± 25 Results shown s men ± SD The phrmcodynmics of single 20 unit dose of HUMALOG U-200 dministered sucutneously were compred to the phrmcodynmics of single 20 unit dose of HUMALOG U-100 dministered sucutneously in euglycemic clmp study enrolling helthy sujects. In this study, the overll, mximum, nd time to mximum glucose lowering effect were similr etween HUMALOG U-200 nd HUMALOG U-100. The men re under the glucose infusion rte curves (mesure of overll phrmcodynmic effect) were 125 g nd 126 g for HUMALOG U-200 nd HUMALOG U-100, respectively. The mximum glucose infusion rte ws 534 mg/min nd 559 mg/min nd the corresponding medin time (min, mx) to mximum effect were 2.8 h (0.5 h 6.3 h) nd 2.4 h (0.5 h 4.7 h) for HUMALOG U-200 nd HUMALOG U-100, respectively Phrmcokinetics Asorption nd Biovilility Studies in helthy volunteers nd ptients with dietes demonstrted tht HUMALOG is sored more quickly thn regulr humn insulin. In helthy volunteers given sucutneous doses of HUMALOG rnging from 0.1 to 0.4 unit/kg, pek serum levels were seen 30 to 90 minutes fter dosing. When helthy volunteers received equivlent doses of regulr humn insulin, pek insulin levels occurred etween 50 to 120 minutes fter dosing. Similr results were seen in ptients with type 1 dietes (see Figure 2). Figure 2: Serum HUMALOG nd Insulin Levels After Sucutneous Injection of Regulr Humn Insulin or HUMALOG (0.2 unit/kg) Immeditely Before High Crohydrte Mel in 10 Ptients with Type 1 Dietes. Bseline insulin concentrtion ws mintined y infusion of 0.2 mu/min/kg humn insulin. HUMALOG U-100 ws sored t consistently fster rte thn regulr humn insulin in helthy mle volunteers given 0.2 unit/kg t dominl, deltoid, or femorl sucutneous sites. After HUMALOG ws dministered in the domen, serum drug levels were higher nd the durtion of ction ws slightly shorter thn fter deltoid or thigh

10 10 dministrtion. Biovilility of HUMALOG is similr to tht of regulr humn insulin. The solute iovilility fter sucutneous injection rnges from 55% to 77% with doses etween 0.1 to 0.2 unit/kg, inclusive. The results of study in helthy sujects demonstrted tht HUMALOG U-200 is ioequivlent to HUMALOG U-100 following dministrtion of single 20 unit dose. The men oserved re under the serum insulin concentrtion-time curve from time zero to infinity ws 2360 pmol hr/l nd 2390 pmol hr/l for HUMALOG U-200 nd HUMALOG U-100, respectively. The corresponding men pek serum insulin concentrtion ws 795 pmol/l nd 909 pmol/l for HUMALOG U-200 nd HUMALOG U-100, respectively. The medin time to mximum concentrtion ws 1.0 hour for oth formultions. Distriution When dministered intrvenously s olus injections of 0.1 nd 0.2 U/kg dose in two seprte groups of helthy sujects, the men volume of distriution of HUMALOG ppered to decrese with increse in dose (1.55 nd 0.72 L/kg, respectively) in contrst to tht of regulr humn insulin for which, the volume of distriution ws comprle cross the two dose groups (1.37 nd 1.12 L/kg for 0.1 nd 0.2 U/kg dose, respectively). Metolism Humn metolism studies hve not een conducted. However, niml studies indicte tht the metolism of HUMALOG is identicl to tht of regulr humn insulin. Elimintion After sucutneous dministrtion of HUMALOG, the t 1/2 is shorter thn tht of regulr humn insulin (1 versus 1.5 hours, respectively). When dministered intrvenously, HUMALOG nd regulr humn insulin demonstrted similr dose-dependent clernce, with men clernce of 21.0 ml/min/kg nd 21.4 ml/min/kg, respectively (0.1 unit/kg dose), nd 9.6 ml/min/kg nd 9.4 ml/min/kg, respectively (0.2 unit/kg dose). Accordingly, HUMALOG demonstrted men t1/2 of 0.85 hours (51 minutes) nd 0.92 hours (55 minutes), respectively for 0.1 unit/kg nd 0.2 unit/kg doses, nd regulr humn insulin men t1/2 ws 0.79 hours (47 minutes) nd 1.28 hours (77 minutes), respectively for 0.1 unit/kg nd 0.2 unit/kg doses. Specific Popultions The effects of ge, gender, rce, oesity, pregnncy, or smoking on the phrmcokinetics of HUMALOG hve not een studied. Renl Impirment Type 2 dietic ptients with vrying degree of renl impirment showed no difference in phrmcokinetics of regulr insulin nd HUMALOG. However, the sensitivity of the ptients to insulin did chnge, with n incresed response to insulin s the renl function declined. Some studies with humn insulin hve shown incresed circulting levels of insulin in ptients with renl impirment. Creful glucose monitoring nd dose djustments of insulin, including HUMALOG, my e necessry in ptients with renl dysfunction. Heptic Impirment Type 2 dietic ptients with impired heptic function showed no effect on the phrmcokinetics of HUMALOG s compred to ptients with no heptic dysfunction. However, some studies with humn insulin hve shown incresed circulting levels of insulin in ptients with liver filure. Creful glucose monitoring nd dose djustments of insulin, including HUMALOG, my e necessry in ptients with heptic dysfunction NONCLINICAL TOXICOLOGY Crcinogenesis, Mutgenesis, Impirment of Fertility Stndrd 2-yer crcinogenicity studies in nimls hve not een performed. In Fischer 344 rts, 12-month repet-dose toxicity study ws conducted with insulin lispro t sucutneous doses of 20 nd 200 units/kg/dy (pproximtely 3 nd 32 times the humn sucutneous dose of 1 unit/kg/dy, sed on units/ody surfce re). Insulin lispro did not produce importnt trget orgn toxicity including mmmry tumors t ny dose. Insulin lispro ws not mutgenic in the following genetic toxicity ssys: cteril muttion, unscheduled DNA synthesis, mouse lymphom, chromosoml errtion nd micronucleus ssys. Mle fertility ws not compromised when mle rts given sucutneous insulin lispro injections of 5 nd 20 units/kg/dy (0.8 nd 3 times the humn sucutneous dose of 1 unit/kg/dy, sed on units/ody surfce re) for 6 months were mted with untreted femle rts. In comined fertility, perintl, nd postntl study in mle nd femle rts given 1, 5, nd 20 units/kg/dy sucutneously (0.16, 0.8, nd 3 times the humn sucutneous dose of 1 unit/kg/dy, sed on units/ody surfce re), mting nd fertility were not dversely ffected in either gender t ny dose Animl Toxicology nd/or Phrmcology In stndrd iologicl ssys in fsted rits, 0.2 unit/kg of insulin lispro injected sucutneously hd the sme glucose-lowering effect nd hd more rpid onset of ction s 0.2 unit/kg of regulr humn insulin. 14 CLINICAL STUDIES The sfety nd efficcy of HUMALOG U-100 were studied in children, dolescent, nd dult ptients with type 1 dietes (n=789) nd dult ptients with type 2 dietes (n=722) Type 1 Dietes Adults nd Adolescents A 12-month, rndomized, prllel, open-lel, ctive-controlled study ws conducted in ptients with type 1 dietes to ssess the sfety nd efficcy of HUMALOG (n=81) compred with Humulin R [REGULAR insulin humn injection, USP (rdna origin)] (n=86). HUMALOG ws dministered y sucutneous injection immeditely prior to mels nd Humulin R ws dministered 30 to 45 minutes efore mels. Humulin U [ULTRALENTE humn insulin (rdna origin) extended zinc suspension] ws dministered once or twice dily s the sl insulin. There ws 2- to 4-week

11 11 run-in period with Humulin R nd Humulin U efore rndomiztion. Most ptients were Cucsin (97%). Forty-seven percent of the ptients were mle. The men ge ws 31 yers (rnge 12 to 70 yers). Glycemic control, the totl dily doses of HUMALOG nd Humulin R, nd the incidence of severe hypoglycemi (s determined y the numer of events tht were not self-treted) were similr in the two tretment groups. There were no episodes of dietic ketocidosis in either tretment group. Tle 5: Type 1 Dietes Mellitus Adults nd Adolescents Tretment Durtion 12 months Tretment in Comintion with: Humulin U HUMALOG N 81 Bseline HA1c (%) 8.2 ± 1.4 Chnge from seline HA1c (%) -0.1 ± 0.9 Tretment Difference in HA1c Men (95% confidence intervl) 0.4 (0.0, 0.8) Bseline short-cting insulin dose (units/kg/dy) 0.3 ± 0.1 End-of-Study short-cting insulin dose (units/kg/dy) 0.3 ± 0.1 Chnge from seline short-cting insulin dose (units/kg/dy) 0.0 ± 0.1 Bseline Body weight (kg) 72 ± 12.7 Weight chnge from seline (kg) 1.4 ± 3.6 Ptients with severe hypoglycemi (n, %) 14 (17%) Vlues re Men ± SD Severe hypoglycemi refers to hypoglycemi for which ptients were not le to self-tret. Humulin R ± ± ± ± ± ± ± (21%) 14.2 Type 2 Dietes Adults A 6-month rndomized, crossover, open-lel, ctive-controlled study ws conducted in insulin-treted ptients with type 2 dietes (n=722) to ssess the sfety nd efficcy of HUMALOG for 3 months followed y Humulin R for 3 months or the reverse sequence. HUMALOG ws dministered y sucutneous injection immeditely efore mels nd Humulin R ws dministered 30 to 45 minutes efore mels. Humulin N [NPH humn insulin (rdna origin) isophne suspension] or Humulin U ws dministered once or twice dily s the sl insulin. All ptients prticipted in 2- to 4week run-in period with Humulin R nd Humulin N or Humulin U. Most of the ptients were Cucsin (88%), nd the numers of men nd women in ech group were pproximtely equl. The men ge ws 58.6 yers (rnge 23.8 to 85 2 yers). The verge ody mss index (BMI) ws 28.2 kg/m. During the study, the mjority of ptients used Humulin N (84%) compred with Humulin U (16%) s their sl insulin. The reductions from seline in HA 1c nd the incidence of severe hypoglycemi (s determined y the numer of events tht were not self-treted) were similr etween the two tretments from the comined groups (see Tle 6). Tle 6: Type 2 Dietes Mellitus Adults Bseline HA1c (%) 8.9 ± 1.7 Chnge from seline HA1c (%) Short-cting insulin dose (units/kg/dy) 0.3 ± 0.2 Chnge from seline short-cting insulin dose (units/kg/dy) Body weight (kg) 80 ± 15 Weight chnge from seline Ptients with severe hypoglycemi (n, %) Vlues re Men ± SD Severe hypoglycemi refers to hypoglycemi for which ptients were not le to self-tret End point HUMALOG Humulin R + + Bsl Bsl 8.2 ± ± ± ± ± ± ± ± ± ± ± ± (2%) 16 (2%) Type 1 Dietes Peditric nd Adolescents An 8-month, crossover study of dolescents with type 1 dietes (n=463), ged 9 to 19 yers, compred two sucutneous multiple-dose tretment regimens: HUMALOG or Humulin R, oth dministered with Humulin N (NPH humn insulin) s the sl insulin. HUMALOG chieved glycemic control comprle to Humulin R, s mesured y HA1c (see Tle 7), nd oth tretment groups hd comprle incidence of hypoglycemi. In 9-month, crossover study of prepuescent children (n=60) with type 1 dietes, ged 3 to 11 yers, HUMALOG dministered immeditely efore mels, HUMALOG dministered immeditely fter mels nd Humulin R dministered 30 minutes efore mels resulted in similr glycemic control, s mesured y HA 1c, nd incidence of hypoglycemi, regrdless of tretment group.

12 12 Tle 7: Peditric Sucutneous Administrtion of HUMALOG in Type 1 Dietes End point Bseline HUMALOG Humulin R + + NPH NPH HA1c (%) 8.6 ± ± ± 1.6 Chnge from seline HA1c (%) 0.1 ± ± 1.3 Short-cting insulin dose (units/kg/dy) 0.5 ± ± ± 0.2 Chnge from seline short-cting insulin dose (units/kg/dy) 0.01 ± ± 0.1 Body weight (kg) 59.1 ± ± ± 12.9 Weight chnge from seline (kg) 2.0 ± ± 3.0 Ptients with severe hypoglycemi (n, %) 5 (1.1%) 5 (1.1%) Dietic ketocidosis (n, %) 11 (2.4%) 9 (1.9%) Vlues re Men ± SD Severe hypoglycemi refers to hypoglycemi tht required glucgon or glucose injection or resulted in com Type 1 Dietes Adults Continuous Sucutneous Insulin Infusion To evlute the dministrtion of HUMALOG U-100 vi externl insulin pumps, two open-lel, crossover design studies were performed in ptients with type 1 dietes. One study involved 39 ptients, ges 19 to 58 yers, treted for 24 weeks with HUMALOG or regulr humn insulin. After 12 weeks of tretment, the men HA1c vlues decresed from 7.8% to 7.2% in the HUMALOG-treted ptients nd from 7.8% to 7.5% in the regulr humn insulin-treted ptients. Another study involved 60 ptients (men ge 39, rnge 15 to 58 yers) treted for 24 weeks with either HUMALOG or uffered regulr humn insulin. After 12 weeks of tretment, the men HA 1c vlues decresed from 7.7% to 7.4% in the HUMALOG-treted ptients nd remined unchnged from 7.7% in the uffered regulr humn insulin-treted ptients. Rtes of hypoglycemi were comprle etween tretment groups in oth studies Type 1 Dietes Peditric Continuous Sucutneous Insulin Infusion A rndomized, 16-week, open-lel, prllel design, study of children nd dolescents with type 1 dietes (n=298) ged 4 to 18 yers compred two sucutneous infusion regimens dministered vi n externl insulin pump: insulin sprt (n=198) or HUMALOG U-100 (n=100). These two tretments resulted in comprle chnges from seline in HA1c nd comprle rtes of hypoglycemi fter 16 weeks of tretment (see Tle 8). Infusion site rections were similr etween groups. Tle 8: Peditric Insulin Pump Study in Type 1 Dietes (16 weeks; n=298) HUMALOG Asprt N Bseline HA1c (%) 8.2 ± ± 0.9 Chnge from Bseline HA1c (%) -0.1 ± ± 0.8 Tretment Difference in HA1c, Men (95% confidence intervl) 0.1 (-0.3, 0.1) Bseline insulin dose (units/kg/24 hours) 0.9 ± ± 0.3 End-of-Study insulin dose (units/kg/24 hours) 0.9 ± ± 0.2 Ptients with severe hypoglycemi (n, %) 8 (8%) 19 (10%) Dietic ketocidosis (n, %) 0 (0) 1 (0.5%) Bseline ody weight (kg) 55.5 ± ± 19.7 Weight Chnge from seline (kg) 1.6 ± ± 2.1 Vlues re Men ± SD Severe hypoglycemi refers to hypoglycemi ssocited with centrl nervous system symptoms nd requiring the intervention of nother person or hospitliztion HOW SUPPLIED/STORAGE AND HANDLING How Supplied HUMALOG 100 units per ml (U-100) is ville s: 10 ml vils 3 ml vils 1 5 x 3 ml crtridges 5 x 3 ml Humlog KwikPen (prefilled) NDC (VL-7510) NDC (VL-7533) NDC (VL-7516) NDC (HP-8799)

13 13 HUMALOG 200 units per ml (U-200) is ville s: 2 x 3 ml Humlog KwikPen (prefilled) NDC (HP-7712) Ech prefilled KwikPen, crtridge, nd reusle pen comptile with Lilly 3 ml crtridges is for use y single ptient. HUMALOG KwikPens, crtridges, nd reusle pens comptile with Lilly 3 ml crtridges must never e shred etween ptients, even if the needle is chnged. Ptients using HUMALOG vils must never shre needles or syringes with nother person Storge nd Hndling Do not use fter the expirtion dte. Unopened HUMALOG should e stored in refrigertor (36 to 46 F [2 to 8 C]), ut not in the freezer. Do not use HUMALOG if it hs een frozen. In-use HUMALOG vils, crtridges, nd HUMALOG KwikPen should e stored t room temperture, elow 86 F (30 C) nd must e used within 28 dys or e discrded, even if they still contin HUMALOG. Protect from direct het nd light. See tle elow: 10 ml vil Not In-Use (Unopened) Not In-Use (Unopened) Room Temperture Refrigerted (Below 86 F [30 C]) HUMALOG U dys Until expirtion dte 3 ml vil 28 dys Until expirtion dte 3 ml crtridge 28 dys Until expirtion dte 3 ml Humlog KwikPen (prefilled) 28 dys Until expirtion dte 3 ml Humlog KwikPen (prefilled) 28 dys HUMALOG U-200 Until expirtion dte In-Use (Opened) Room Temperture, (Below 86 F [30 C]) 28 dys, refrigerted/room temperture. 28 dys, refrigerted/room temperture. 28 dys, Do not refrigerte. 28 dys, Do not refrigerte. 28 dys, Do not refrigerte. Use in n Externl Insulin Pump Chnge the HUMALOG U-100 in the reservoir t lest every 7 dys, chnge the infusion sets nd the infusion set insertion site t lest every 3 dys or fter exposure to tempertures tht exceed 98.6 F (37 C). A HUMALOG 3 ml crtridge used in the D-Tron pumps should e discrded fter 7 dys, even if it still contins HUMALOG. However, s with other externl insulin pumps, the infusion set should e replced nd new infusion set insertion site should e selected t lest every 3 dys. Diluted HUMALOG U-100 for Sucutneous Injection Diluted HUMALOG my remin in ptient use for 28 dys when stored t 41 F (5 C) nd for 14 dys when stored t 86 F (30 C). Do not dilute HUMALOG contined in crtridge or HUMALOG used in n externl insulin pump Preprtion nd Hndling Diluted HUMALOG U-100 for Sucutneous Injection HUMALOG my e diluted with Sterile Diluent for HUMALOG for sucutneous injection. Diluting one prt HUMALOG to nine prts diluent will yield concentrtion onetenth tht of HUMALOG (equivlent to U-10). Diluting one prt HUMALOG to one prt diluent will yield concentrtion one-hlf tht of HUMALOG (equivlent to U-50) Admixture for Intrvenous Administrtion Infusion gs prepred with HUMALOG U-100 re stle when stored in refrigertor (2 to 8 C [36 to 46 F]) for 48 hours nd then my e used t room temperture for up to n dditionl 48 hours [see Dosge nd Administrtion (2.2)]. 17 PATIENT COUNSELING INFORMATION Advise the ptient to red the FDA-pproved ptient leling (Ptient Informtion nd Instructions for Use) Never Shre HUMALOG KwikPen, Crtridge, Reusle Pen Comptile with Lilly 3 ml Crtridges, or Syringe Between Ptients Advise ptients tht they must never shre HUMALOG KwikPen, crtridge, or reusle pen comptile with Lilly 3 ml crtridges with nother person, even if the needle is chnged. Advise ptients using HUMALOG vils not to shre needles or syringes with nother person. Shring poses risk for trnsmission of lood-orne pthogens Hypoglycemi Instruct ptients on self-mngement procedures including glucose monitoring, proper injection technique, nd mngement of hypoglycemi nd hyperglycemi, especilly t initition of HUMALOG therpy. Instruct ptients on hndling of specil situtions such s intercurrent conditions (illness, stress, or emotionl disturnces), n indequte or

14 14 skipped insulin dose, indvertent dministrtion of n incresed insulin dose, indequte food intke, nd skipped mels. Instruct ptients on the mngement of hypoglycemi. Inform ptients tht their ility to concentrte nd rect my e impired s result of hypoglycemi. Advise ptients who hve frequent hypoglycemi or reduced or sent wrning signs of hypoglycemi to use cution when driving or operting mchinery [see Wrnings nd Precutions (5.3)] Hypersensitivity Rections Advise ptients tht hypersensitivity rections hve occurred with HUMALOG. Inform ptients on the symptoms of hypersensitivity rections [see Wrnings nd Precutions (5.5)] Mediction Errors Instruct ptients to lwys check the insulin lel efore ech injection to void mix-ups etween insulin products. Inform ptients tht HUMALOG U-200 contins 2 times s much insulin in 1 ml s HUMALOG U-100. Inform ptients tht the HUMALOG U-200 KwikPen dose window shows the numer of units of HUMALOG U-200 to e injected nd tht no dose conversion is required. Instruct ptients to NOT trnsfer HUMALOG U-200 from the HUMALOG KwikPen to syringe. The mrkings on the syringe will not mesure the dose correctly nd this cn result in overdosge nd severe hypoglycemi Administrtion Instruction for HUMALOG U-200 Instruct ptients to NOT mix HUMALOG U-200 with ny other insulin Women of Reproductive Potentil Advise femles of reproductive potentil with dietes to inform their doctor if they re pregnnt or re contemplting pregnncy [see Use in Specific Popultions (8.1)] Instructions For Ptients Using Continuous Sucutneous Insulin Pumps Ptients using externl pump infusion therpy should e trined ppropritely. The following insulin pumps hve een tested in HUMALOG clinicl trils conducted y Eli Lilly nd Compny. 2 Disetronic H-Tron plus V100, D-Tron nd D-Tronplus with Disetronic Rpid infusion sets 3 MiniMed Models 506, 507 nd 508 nd Polyfin infusion sets HUMALOG is recommended for use in pump systems suitle for insulin infusion such s MiniMed, Disetronic, nd other equivlent pumps. Before using HUMALOG in pump system, red the pump lel to mke sure the pump is indicted for continuous delivery of fst-cting insulin. HUMALOG is recommended for use in ny reservoir nd infusion sets tht re comptile with insulin nd the specific pump. Plese see recommended reservoir nd infusion sets in the pump mnul. Do not use HUMALOG U-200 in n externl insulin pump. To void insulin degrdtion, infusion set occlusion, nd loss of the preservtive (metcresol), insulin in the reservoir should e replced t lest every 7 dys; infusion sets nd infusion set insertion sites should e chnged t lest every 3 dys. Insulin exposed to tempertures higher thn 98.6 F (37 C) should e discrded. The temperture of the insulin my exceed mient temperture when the pump housing, cover, tuing or sport cse is exposed to sunlight or rdint het. Infusion sites tht re erythemtous, pruritic, or thickened should e reported to the helthcre professionl, nd new site selected ecuse continued infusion my increse the skin rection or lter the sorption of HUMALOG. Pump or infusion set mlfunctions or insulin degrdtion cn led to rpid hyperglycemi nd ketosis. This is especilly pertinent for rpid cting insulin nlogs tht re more rpidly sored through skin nd hve shorter durtion of ction. Prompt identifiction nd correction of the cuse of hyperglycemi or ketosis is necessry. Prolems include pump mlfunction, infusion set occlusion, lekge, disconnection or kinking, nd degrded insulin. Less commonly, hypoglycemi from pump mlfunction my occur. If these prolems cnnot e promptly corrected, ptients should resume therpy with sucutneous insulin injection nd contct their helthcre professionls [see Dosge nd Administrtion (2.2) nd How Supplied/Storge nd Hndling (16.2)]. 1 3 ml crtridge is for use in Eli Lilly nd Compny s HumPen Luxur HD insulin delivery device, Disetronic D-TRON nd D-TRON Plus pumps. Humlog, Humlog KwikPen, HumPen, HumPen Luxur nd HumPen Luxur HD re registered trdemrks of Eli Lilly nd Compny. 2 Disetronic, H-Tron, D-Tron, nd D-Tronplus re registered trdemrks of Roche Dignostics GmH. 3 MiniMed nd Polyfin re registered trdemrks of MiniMed, Inc. Other product nd compny nmes my e the trdemrks of their respective owners. Literture revised Novemer 16, 2015 Mrketed y: Lilly USA, LLC, Indinpolis, IN 46285, USA Copyright 1996, 2015, Eli Lilly nd Compny. All rights reserved. LOG-0004-USPI